Macrolide Polymorphs, Compositions Comprising Such Polymorphs, and Methods of Use and Manufacture Thereof

Abstract

The invention relates to novel forms of compounds displaying broad spectrum antibiotic activity, especially crystalline polymorphic forms and amorphous forms of such compounds, compositions comprising such crystalline polymorphic forms and amorphous forms of such compounds, processes for manufacture and use thereof. The compounds and compositions of the invention are useful in the pharmaceutical industry, for example, in the treatment or prevention of diseases or disorders associated with the use of antibiotics, chemotherapies, or antiviral therapies, including, but not limited to, colitis, for example, pseudo-membranous colitis; antibiotic associated diarrhea; and infections due to Clostridium difficile (“ C. difficile ”), Clostridium perfringens (“ C. perfringens ”), Staphylococcus species, for example, methicillin-resistant Staphylococcus , or Enterococcus including Vancomycin-resistant enterococci.

What is claimed is: 
     
         1 . A crystalline polymorph of tiacumicin comprising a powder x-ray diffraction pattern with at least peaks at diffraction angles 2θ of 7.7°, 15.0°, and 18.8°±0.2. 
     
     
         2 . The crystalline polymorph of  claim 1 , comprising a polymorph having the chemical structure of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The crystalline polymorph of  claim 2 , further comprising at least one compound selected from a mixture of tiacumicins. 
     
     
         4 . The crystalline polymorph of  claim 2 , wherein the polymorph of Formula I is present in at least about 75% to about 99.99%. 
     
     
         5 . The crystalline polymorph of  claim 4 , wherein the polymorph of Formula I is present in at least about 85%. 
     
     
         6 . The crystalline polymorph of  claim 4 , wherein the polymorph of Formula I is present in at least about 90%. 
     
     
         7 . The crystalline polymorph of  claim 4 , wherein the polymorph of Formula I is present in at least about 95%. 
     
     
         8 . The crystalline polymorph of  claim 4 , wherein the polymorph of Formula I is present in at least about 99%. 
     
     
         9 . A crystalline polymorph of tiacumicin comprising:
 (i) a DSC endotherm in the range of about 174° C. to about 186° C.; and   (ii) a chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
     
     
         10 . The crystalline polymorph of  claim 9 , further comprising at least one compound selected from a mixture of tiacumicins. 
     
     
         11 . The crystalline polymorph of  claim 9 , wherein the polymorph of Formula I is present from about 75% to about 99.99%. 
     
     
         12 . The crystalline polymorph of  claim 9 , wherein the polymorph of Formula I is present in at least about 85%. 
     
     
         13 . The crystalline polymorph of  claim 11 , wherein the polymorph of Formula I is present in at least about 90%. 
     
     
         14 . The crystalline polymorph of  claim 11 , wherein the polymorph of Formula I is present in at least about 95%. 
     
     
         15 . The crystalline polymorph of  claim 11 , wherein the polymorph of Formula I is present in at least about 99%. 
     
     
         16 . A crystalline polymorph of tiacumicin comprising:
 (i) a powder x-ray diffraction pattern with at least peaks at diffraction angles 2θ of 7.7°, 15.0°, and 18.8°±0.2;   (ii) a DSC endotherm in the range of about 174° C. to about 186° C.; and   (iii) a chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
     
     
         17 . The crystalline polymorph of  claim 16 , further comprising at least one compound selected from a mixture of tiacumicins. 
     
     
         18 . The crystalline polymorph of  claim 16 , wherein the Compound of Formula I is present from about 75% to about 99.99%. 
     
     
         19 . The crystalline polymorph of  claim 16 , wherein the Compound of Formula I is present in about 90%. 
     
     
         20 . A composition comprising the crystalline polymorph of  claim 1  and a pharmaceutically acceptable carrier.